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Removable directing groups

18 December 2010 - Org. Synth. Strategy

Regioselectivity in aromatic electrophilic substitution continues to attract chemical research even though the reaction is over 100 years old. The problem is this regioselectivity can be difficult to achieve. Take a monosubstituted arene, throw a chemical at it and see where it ends up. In a totally unspecific reaction the new substituent can occupy one of 3 different positions (ortho, meta or para) and with multiple substitutions the mix gets even more complicated. Regioselectivity can be introduced by so-called directing groups. Activating groups promote ortho and meta substitution and deactivating groups that of meta substitution. But what to do with them when the reaction is done?. An old trick that gets rediscovered from time to time is the use of a removable directing group. A classic is the sulfonic acid group in aromatic sulfonation or the carboxyl group. Recent case studies involving removable directing group are those on pyridyl silyl groups DOI, carboxyl groups DOI and cyano groups DOI.

In a most recent exploit Alvarez-Bercedo and Martin have investigated the aryl ether group as a potential removable directing group (DOI). The structure 7 in the scheme below is a naphthalene with a carboxylic ester group at position 1 and a phenyl group at position 5. Apparently raw materials 1-carboxylnaphthalene or 3-phenylnaphthalene have the wrong directing groups at the wrong places so a cunning plan is required that features 2-naphthol 1. A sequence of reaction steps then takes place creating the desired substituents as follows: carboxylation to 2 (carbon dioxide/potassium hydroxide), esterification to 3 (dimethyl sulfate / lithium hydroxide), bromination to 4 (bromine / acetic acid), alkylation to 5 (dimethyl sulfate / potassium carbonate) and phenyl Suzuki coupling to 6 (phenylboronic acid / palladium acetate / SPhos / tripotassium phosphate).

In the final surprise step the methoxy group has played its role and is removed by dimethyldisoloxane as hydrogen donor and Nickel bis(cyclooctadiene) / tricyclohexylphosphine as catalyst. As an encore Alvarez-Bercedo and Martin and prooved the silicon compound truly is the hydrogen donor by applying a deuterated one.
CO bond reduction Martin 2010

Platencimycin relay

15 December 2010 - Total synthesis

platensimycin magnus 2010  A new route to an existing intermediate in the total synthesis of natural antibiotic platencimycin as reported by Magnus/Rivera/Lynch (Org. Lett. 2010). See previous posts here and here. As always in this type of work for each synthetic step many methods exist but only one will work as this report nicely illustrates.

Known spiroketone 1 was reacted with methylmagnesium chloride (THF, -78°C) to alcohol 2 .MeLi did not work: enolization of the other keto group. Reaction with t-BuOK / t-BuOH and MeI gave alpha-methylketone 3, oxidation of which (oxygen, tetra-n-butylammonium bromide, KOH, t-BuOH) gave diol 4. Trimethyl phosphite did not work: secondary peroxide reactions. Enone reduction (LiAl2H2(OEt)2, THF, -78°C) gave 5 with correct stereochemistry . Finally reaction in DMSO (170°C, microwave) gave ether 6. TFA did not work: epimerization at the alcohol group.

Novel carbide anion sighting

12 December 2010 - Inorganic chemistry

In the animal world new species are discovered on a regular basis and the sighting of a rare species (the double tailed pigeon or purple Chichi-Sima tunicate) too may provoke media attention. So too in chemistry: David A. Lang et al. of Florida State University have stumbled on a rare sighting of the C34- anion of the carbide family and reports about it in the latest issue of JACS (DOI). The group's research actual target was a light-weight metal flux for use in alloys and as hydrogen storage material. A regular carbide is of the type MC2 such as calcium carbide with the carbon segment a deprotonated acetylide. The rare C3 fragment is called a sesquicarbide and can be found for example in Sc3C4. It can be regarded as a deprotonated allene.

The novel carbide (formally (Ca2+)2Li+(C3)4-(H-)) was synthesized by heating a mixture of calcium shot, lithium rod , carbon black and calcium hydride (10/10/6/1) at 1323 K. The product forms as 1 mm sized crystals in a Li/Ca melt that can be isolated by centrifugation. As expected in the solid state the C3 fragment is linear with C-C distance (132 pm) consistent with an allene. The calcium ions are present not only as an extension of the C3 unit but also perpendicular to it (pic). Lithium and hydrogen are present as alternating chains making it a double salt as in (Ca2C3)(LiH). Calcium and carbon alone will not form the C3 carbide. The new compound is oxidation prone and (violent) reaction with water yields allene itself.

Chemical bonds to carbon

11 December 2010 - Wikipedia curation project IV

In the fourth part of our wikibook chemistry curation project again dozens of Wikipedia editors have contributed to bring you the ultimate wikibook this time on the elements and their bonds to carbon. The idea is simple: the periodic table contains abut 100 relevant elements and most of them bond to carbon in one way or another. The implications of the carbon-hydrogen bond and the carbon-nitrogen bond are pretty obvious but what about organoantimony chemistry or group 2 organometallic chemistry?. Traditionally organometallic chemistry is a distinct branch of chemistry but not this overview: organochromium chemistry and organosilver chemistry are accounted for and organolanthanide chemistry is in the making. And if you are into totally obscure chemistry there is organouranium chemistry. Unfortunately chemists are not philosophically inclined and do not expect a theory-of-everything as a result of these pages. It is a start anyway.

Open here: Wikibooks/Isomerism.pdf (8.5 MB, 120 pages)
Open here: Wikibooks/Organic_Reactions.pdf (10 MB, 184 pages)
Open here: Wikibooks/Functional_groups.pdf (12 MB, 167 pages)
Open here: Wikibooks/chemical_bonds_to_carbon.pdf (6 MB, 143 pages)

Next up: the wonders of Total Synthesis!

Metal free (?) coupling reactions

03 December 2010 - OrgaNOmetalllic chemistry

metal free aryl coupling Sun 2010  The pun orgaNOmetallic chemistry in the intro text is courtesy of Nicholas Leadbeater who is discussing the merits of metal-free coupling reactions in an essay accompanying a research article by Sun et al. in Nature Chemistry (DOI). An earlier blog introduced Leadbeater advocating a metal-free Sonogashira reaction back in 2003. But these so-called metal-free reactions raise suspicions because minute quantities of metal may be present in any solvent or reagent , see for example the findings of Buchwald & Bolm in another blog. In his essay Leadbeater explains the preparations for the 2003 experiment were meticulous with an (unfortunate) student performing the reaction quarantined (but for how long!) in demetallized laboratory fitted with new glassware and fresh reagents. But when the lab moved from England to the US the reaction started to behave oddly and eventually traces (50ppb) of palladium were found lurking in the sodium carbonate.

Nevertheless Leadbeater fully supports the new Sun et al. research. They reacted bromoanisole with benzene (the solvent) in the presence of potassium tert-butoxide and a catalytic amounts of phenanthroline. Traces of Pd, Cu and Fe (10 ppb - 10 ppm) were found in the reagents using ICP-MS but deliberately adding these metals in larger quantities to the reaction did not improve conversion. They also had the reaction performed in other laboratories just to be sure.

Also in 2010 Liu et al. (DOI) used potassium tert-butoxide and another diamine N,N-dimethyl-ethylenediamine in a very similar reaction. Earlier in 2008 Yanagisawa et al. had already noted that nitrogen heterocycles could be coupled with just the base (DOI) In all reports the proposed mechanism is based on a aryl radical anion intermediate. In the Sun report the amine and butoxide base can be replaced by trusted radical initiators azobisisobutyronitrile and tributyltin hydride.